A novel series of 4-phenyl-4-[1H-imidazol-2-yl]-piperidine derivatives has been prepared and their synthesis described herein. In vitro affinities for delta-, mu-, and kappa-opioid receptors, as well as the functional activity in the [S-35]GTP gamma S assay are reported. The most potent and selective delta-opioid agonist 18a exhibited a K-i of 18 nM, and was > 258-fold and 28-fold selective over mu- and kappa-receptors, respectively; the compound is a full agonist with an EC50 value of 14 nM. (c) 2005 Elsevier Ltd. All rights reserved.